[ CAS No. 34551-41-2 ] {[proInfo.proName]}

Name: 34551-41-2|5-Bromo-1-chloroisoquinoline|95%
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Quality Control of [ 34551-41-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 34551-41-2 ]

CAS No. :	34551-41-2	MDL No. :	MFCD08703278
Formula :	C₉H₅BrClN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XUWFLTLTPVIRCV-UHFFFAOYSA-N
M.W :	242.50	Pubchem ID :	21192497
Synonyms :

Safety of [ 34551-41-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 34551-41-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 34551-41-2 ]
Downstream synthetic route of [ 34551-41-2 ]

[ 34551-41-2 ] Synthesis Path-Upstream 1~3

1
[ 34784-04-8 ]
[ 34551-41-2 ]

Yield	Reaction Conditions	Operation in experiment
33 g	Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 40℃; for 20 h; Stage #2: With trichlorophosphate In dichloromethane at 45℃; for 18 h;	To a solution of 2 (60 g, 288 mmoles) in methylene chloride (1.5 L) there are added (75 g, 436 mmoles) of 75percent m-CPBA. The mixture is heated at 40° C. for 20 hours. After HPLC monitoring and return to ambient temperature, 75 g of sodium thiosulphate are added in the course of 10 minutes, followed by 300 mL of water. The whole is decanted, the organic phase is washed with a 1N sodium hydroxide solution, and the organic phase is dried by passage over MgSO₄. Evaporation under reduced pressure yields a white solid (42 g), which is used without additional treatment in the following step. A solution of the intermediate that forms (37 g, 165 mmoles) in methylene chloride (900 mL) and POCl₃(37 mL) is stirred for 18 hours at 45° C. After HPLC and/or GC monitoring, the reaction mixture is concentrated in vacuo. The residue is treated carefully with water, and the aqueous phase is extracted with methylene chloride. The organic phase is washed carefully with a saturated NaHCO₃solution and then with a saturated aqueous NaCl solution. Evaporation under reduced pressure yields intermediate 123 (33 g) in the form of a beige solid, which can be used without additional treatment in the following step. ¹H NMR (400 MHz-CDCl₃): δ 8.35 (2d, 2H), 8.00 (2d, 2H), 7.55 (t, 1H) GC-EI (70 eV): M+.=241

Reference： [1] Patent: US2013/296320, 2013, A1,
[2] Patent: WO2016/201052, 2016, A1,
[3] Patent: US2017/137385, 2017, A1, . Location in patent: Paragraph 0203; 0204; 0205; 0206

2
[ 34551-41-2 ]
[ 215453-51-3 ]

Reference： [1] Patent: US6248738, 2001, B1,

3
[ 34551-41-2 ]
[ 852570-80-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With ammonia In methanol at 180℃; for 360 h; In autoclave	A suspension of5-bromo-1-chloroisoquinoline (2.0 g, 8.25mmol) in sat. NH3-MeOH (100 mL) was heated to180 C for 15days in autoclave. After cooling, the solvent was removed by evapolation. The residue was washed with CH2CI2 then purified on SCX SPE. Formed solid was washed with hexane to give the title compound (1.57 g, 85percent).
85%	With ammonia In methanol at 180℃; for 360 h; In autoclave	A suspension of5-bromo-1-chloroisoquinoline (4) (2.0 g, 8.25mmol) in sat. NH3-MeOH (100 mL) was heated to180 C for 15days in an autoclave. After cooling, the solvent was removed by evaporation. The residue was washed withCH2CI2 then purified on SCX SPE. Formed solid was washed with hexane to give the title compound (1.57g, 85 percent). MS (ESI) (M+H)+ 223,225.
75%	at 180℃; for 3 h; Inert atmosphere	Step 3: Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a mixture of 5-bromo-1-chloroisoquinoline (17.5 g, 72.16mmol, 1.00 equiv), AcNH2 (85.8 g, 1.45 mol, 20.15 equiv) and potassium carbonate (49.0 g,354.53 mmol, 4.91 equiv). The mixture was stirred for 3 h at 180 °C then it was cooled to RT and poured into 2000 mL of water with stirring. The solids were collected by filtration toprovide 12.0 g (75percent) of 5-bromoisoquinolin-1-amine as a brown solid.

Reference： [1] Patent: WO2005/49576, 2005, A1, . Location in patent: Page/Page column 29
[2] Patent: WO2005/49577, 2005, A1, . Location in patent: Page/Page column 32-33
[3] Patent: WO2016/201052, 2016, A1, . Location in patent: Page/Page column 272
[4] Patent: WO2008/86014, 2008, A2, . Location in patent: Page/Page column 60

[ 34551-41-2 ] Synthesis Path-Downstream 1~69

3
[ 34551-41-2 ]
[ 50-01-1 ]
<i>N</i>-(5-bromo-isoquinolin-1-yl)-guanidine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3227 - 3230

4
[ 34551-41-2 ]
[ 852570-80-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With ammonia; In methanol; at 180℃; for 360h;In autoclave;	A suspension of5-bromo-1-chloroisoquinoline (2.0 g, 8.25mmol) in sat. NH3-MeOH (100 mL) was heated to180 C for 15days in autoclave. After cooling, the solvent was removed by evapolation. The residue was washed with CH2CI2 then purified on SCX SPE. Formed solid was washed with hexane to give the title compound (1.57 g, 85%).
85%	With ammonia; In methanol; at 180℃; for 360h;In autoclave;	A suspension of5-bromo-1-chloroisoquinoline (4) (2.0 g, 8.25mmol) in sat. NH3-MeOH (100 mL) was heated to180 C for 15days in an autoclave. After cooling, the solvent was removed by evaporation. The residue was washed withCH2CI2 then purified on SCX SPE. Formed solid was washed with hexane to give the title compound (1.57g, 85 %). MS (ESI) (M+H)+ 223,225.
75%	With acetamide; potassium carbonate; at 180℃; for 3h;Inert atmosphere;	Step 3: Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a mixture of 5-bromo-1-chloroisoquinoline (17.5 g, 72.16mmol, 1.00 equiv), AcNH2 (85.8 g, 1.45 mol, 20.15 equiv) and potassium carbonate (49.0 g,354.53 mmol, 4.91 equiv). The mixture was stirred for 3 h at 180 C then it was cooled to RT and poured into 2000 mL of water with stirring. The solids were collected by filtration toprovide 12.0 g (75%) of 5-bromoisoquinolin-1-amine as a brown solid.

With acetamide; potassium carbonate; at 200℃; for 1.5h;

Example 35:5-romoisoquinolin-l-amine. Acetamide (4.9 g, 82 mmol), 5-bromo-l- chloroisoquinoline (1.00 g, 4.1 mmol) and K2CO3 (2.8 g, 21 mmol) were combined in a sealaed tube and the mixture heated at 200 C for 1.5 h. The mixture was allowed to cool to rt and the solid residue suspended in 400 mL water. The brown solid was collected as the title compound (750 mg). MS (ESI pos. ion) m/z: 223 (MH+). Calc'd exact mass for C9H7BrN2 : 223.

Reference： [1]Patent: WO2005/49576,2005,A1 .Location in patent: Page/Page column 29
[2]Patent: WO2005/49577,2005,A1 .Location in patent: Page/Page column 32-33
[3]Patent: WO2016/201052,2016,A1 .Location in patent: Page/Page column 272
[4]Patent: WO2008/86014,2008,A2 .Location in patent: Page/Page column 60

5
[ 580-15-4 ]
[ 34551-41-2 ]
[ 852570-81-1 ]

Yield	Reaction Conditions	Operation in experiment
78%		To a suspension of <strong>[34551-41-2]5-bromo-1-chloroisoquinoline</strong> (3.0 g, 12.4 mmol) in iPrOH (100 mL), 6-aminoquinoline (4.5 g, 31.2 mmol), 4M HCI-dioxane (5 mL) and MeOH (15 mL) were added and stirred at 80 C 3dys. After cooling, the mixture was evaporated to remove solvent then suspended into AcOEt. The mixture was basified with NaHCO3aq. then formed precipitate was collected by filtration and washed with AcOEt to give the title compound (3.4 g, 78%).
78%		To a suspension of<strong>[34551-41-2]5-bromo-1-chloroisoquinoline</strong> (4) (3.0 g, 12.4mmol) iniPrOH (100 mL), 6-aminoquinoline (4.5g, 31.2mmol), 4MHCI-dioxane (5 mL) andMeOH (15 mL) were added and stirred at80 C for 3 days. After cooling, the mixture was evaporated to remove solvent then suspended into AcOEt. The mixture was basified withNaHC03aq. then formed precipitate was collected by filtration and washed with AcOEt to give the title compound (5) (3.4 g, 78 %). MS (ESI) (M+H) + 350,352.

Reference： [1]Patent: WO2005/49576,2005,A1 .Location in patent: Page/Page column 30
[2]Patent: WO2005/49577,2005,A1 .Location in patent: Page/Page column 29

6
5-bromoisoquinolin-2-ium-2-olate [ No CAS ]
[ 34551-41-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With trichlorophosphate; In dichloromethane; at 45℃;Inert atmosphere;	Step 2: Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of 5-bromoisoquinolin-2-ium-2-olate (16.5 g, 73.64 mmol, 1.00 equiv) and POC13 (27.1 g, 176.74 mmol, 2.40 equiv) in dichloromethane(300 mL). The resulting mixture was stirred overnight at 45 C then it was cooled to RT andconcentrated. The residue was treated cautiously with 500 mL of icy water and extracted with3 x 500 mL of dichloromethane. The cornbined organic layer was washed with 500 rnL ofsaturated sodiurn bicarbonate aqueous solution, 500 mL of brine, dried over anhydrous sodiurn sulfate and concentrated under vacuurn to deliver 17.5 g (98%) of 5-bromo-1- chloroisoquinoline as a yellow solid.
74%	With trichlorophosphate; In dichloromethane; at 45℃;	To a solution of 5-bromoisoquinoline N-oxide (20.1 g, 89.5mmol) inCH2CI2 (500 mL), POCI3 (20 mL, 215mmol) was added and stirred at45 C overnight. After cooling, the mixture was evaporated to remove POCI3 then added water. The mixture was extracted with CH2CI2. The organic layer was washed withNaHCO3aq., dried overNa2SO4 then evaporated. Formed solid was washed withMeOH to give the title compound (16.1 g, 74%).
74%	With trichlorophosphate; In dichloromethane; at 45℃;	To a solution of 5-bromoisoquinoline N-oxide (3) (20.1 g, 89.5mmol) inCH2CI2 (500mL),POCI3 (20 mL, 215mmol) was added and stirred at45 C overnight. After cooling, the mixture was evaporated to remove POCI3 then added water. The mixture was extracted withCH2CI2. The organic layer was washed with NaHCO3aq., dried over Na2SO4 then evaporated. Formed solid was washed withMeOH to give the title compound (16.1g, 74 %). MS (ESI) (M+H)+ 242,244, 246

65%		Phosphorus oxychloride (5 ml) was added to a suspension of compound ( 1a) (7.83 g) in chloroform (120 ml), and the mixture was stirred overnight at 50 C. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and small amounts of chloroform and diethyl ether were added to the residue. The deposit was filtrated to obtain compound ( 1b) (5.83 g, 65%) as a white solid.
56%	With trichlorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 0 - 25℃;Inert atmosphere;	General procedure: To a stirred solution of the appropriate azine N-oxides in anhydrous CH2Cl2 (0.1M) at 0 C is added POCl3 (1.2 equiv) followed by dropwise addition of DMF (0.5 equiv) under argon. The resulting reaction mixture was warmed to 25 C and stirred for several hours until the reaction is complete as indicated by TLC. Saturated aqueous sodium carbonate solution is added to the reaction mixture slowly to adjust the pH to 7~8. The resulting mixture is separated and the aqueous phase is extracted with CH2Cl2 thoroughly. The organic phase is combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product, which is purified by flash column chromatography using PE/EA (80:1) as eluent.
	With trichlorophosphate; In water; ethyl acetate;	REFERENCE EXAMPLE 12 To phosphorous oxychloride (1.4 ml) was added 5-bromoisoquinoline-2-oxide (0.28 g), and the mixture was heated to 100 C. for an hour. The mixture was evaporated under reduced pressure. The residue was taken up into a mixture of ethyl acetate and water and the pH of the mixture was adjusted to around 7.5 with an aqueous sodium hydroxide solution. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was triturated with diisopropyl ether to give 1-chloro-5-bromoisoquinoline (0.281 g). APCI-mass; 242, 244 (m/z, [M+H]+), NMR (DMSO-d6, delta): 7.76 (1H, t, J=7.7 Hz), 8.02 (1H, d, J=5.8 Hz), 8.29 (1H, d, J=7.7 Hz), 8.36 (1H, d, J=7.7 Hz), 8.47 (1H, d, J=5.8 Hz).
	With trichlorophosphate; In dichloromethane; at 45℃; for 4h;	Example 34:5-Bromo-l-chloroisoquinoline. To a solution of 5-bromoisoquinoline-N-oxide (4.56 g, 20.4 mmol) in 100 mL CH2Cl2, phosphorus oxychloride (4.17 ml, 44.8 mmol) was added and the mixture heated at 45 C for 4 h. The mixture was allowed to cool and evaporated. Water and ice were added alternating, portion-wise and CH2Cl2 was added to the mixture. The organic layer was made pH 14 with 1 M NaOH, and the organic layer washed with <n="61"/>sat. NaHCO3, dried over Na2SO4, filtered and evaporated. The solid was triturated with methanol and the title compound collected as a fluffy off-white solid (3.93 g). MS (ESI pos. ion) m/z: 242 (MH+). Calc'd exact mass for C9H5BrClN : 242.

Reference： [1]Patent: WO2016/201052,2016,A1 .Location in patent: Page/Page column 271; 272
[2]Patent: WO2005/49576,2005,A1 .Location in patent: Page/Page column 29
[3]Patent: WO2005/49577,2005,A1 .Location in patent: Page/Page column 28-29
[4]Patent: US2013/296320,2013,A1 .Location in patent: Paragraph 0180
[5]Tetrahedron Letters,2014,vol. 55,p. 7130 - 7132
[6]Patent: US2003/176454,2003,A1
[7]Patent: WO2008/86014,2008,A2 .Location in patent: Page/Page column 59-60
[8]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1074 - 1080

7
[ 34551-41-2 ]
aqueous potassium carbonate [ No CAS ]
[ 112677-67-5 ]
[ 374555-34-7 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; ethyl acetate;	EXAMPLE 13 A mixture of <strong>[34551-41-2]1-chloro-5-bromoisoquinoline</strong> (65 mg) and 3-(imidazol-1-yl)aniline (86 mg) was heated to 190 C. for 5 minutes. After cooling to ambient temperature, the reaction mixture was taken up into a mixture of ethyl acetate and an aqueous potassium carbonate solution (10%). The separated organic layer was washed with brine, dried over potassium carbonate and evaporated under reduced pressure. The residue was purified by a column chromatography on silica gel (50 ml) eluding with 0-3% methanol in dichloromethane to give (5-bromoisoquinolin-1-yl)-[3-(imidazol-1-yl)phenyl]amine (54 mg). APCI-mass; 365, 367 (m/z, [M+H]+) NMR (DMSO-d6, delta): 7.13 (1H, s), 7.23-7.67(4H, m), 7.68 (1H, s), 7.85 (1H, d, J=9.1 Hz), 8.08-8.28 (4H, m), 8.60 (1H, d, J=8.3 Hz), 9.52 (1H, s).

Reference： [1]Patent: US2003/176454,2003,A1

8
[ 333792-46-4 ]
[ 34551-41-2 ]
aqueous potassium carbonate [ No CAS ]
[ 374555-35-8 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; ethyl acetate;	EXAMPLE 14 A mixture of <strong>[34551-41-2]1-chloro-5-bromoisoquinoline</strong> (52 mg) and 3-(2,3-dimethyl-3H-imidazol-4-yl)aniline (80 mg) was heated to 190 C. for an hour. After cooling to ambient temperature, the reaction mixture was taken up into a mixture of ethyl acetate and an aqueous potassium carbonate solution (10%). The separated organic layer was washed with brine, dried over potassium carbonate and evaporated under reduced pressure. The residue was purified by a column chromatography on silica gel (50 ml) eluding with 0-3% methanol in dichloromethane to give (5-bromoisoquinolin-1-yl)-[3-(2,3-dimethyl-3H-imidazol-4-yl)phenyl]amine (23 mg). APCI-mass; 393, 395 (m/z, [M+H]+) NMR (DMSO-d6, delta): 2.37 (3H, s), 3.59 (3H, s), 6.87 (1H, s), 7.07 (1H, d, J=7.6 Hz), 7.30-7.47 (2H, m), 7.56 (1H, t, J=7.8 Hz), 7.83 (1H, d, J=7.6 Hz), 7.94 (1H, s), 8.03-8.23 (2H, m), 8.59 (1H, d, J=8.5 Hz), 9.42 (1H, s).

Reference： [1]Patent: US2003/176454,2003,A1

9
[ 34551-41-2 ]
aqueous potassium carbonate [ No CAS ]
[ 69491-59-4 ]
[ 374555-37-0 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; ethyl acetate;	EXAMPLE 16 A mixture of <strong>[34551-41-2]1-chloro-5-bromoisoquinoline</strong> (71 mg) and 3-(pyrimidin-5-yl)-phenylamine (100 mg) was heated to 190 C. for 10 minutes. After cooling to ambient temperature, the reaction mixture was taken up into a mixture of ethyl acetate and an aqueous potassium carbonate solution (10%). The separated organic layer was washed with brine, dried over potassium carbonate and evaporated under reduced pressure. The residue was purified by a column chromatography on silica gel (60 ml) eluding with 0-3% methanol in dichloromethane to give (5-bromoisoquinolin-1-yl)-[3-(pyrimidin-5-yl)phenyl]amine (42 mg). APCI-mass; 377, 379 (m/z, [M+H]+) NMR (DMSO-d6, delta): 7.36 (1H, d, J=6.1 Hz), 7.40-7.70 (3H, m), 7.94-8.31 (4H, m), 8.61 (1H, d, J=8.4 Hz), 9.14 (2H, s), 9.22 (1H, s), 9.49 (1H, s).

Reference： [1]Patent: US2003/176454,2003,A1

10
[ 34551-41-2 ]
aqueous potassium carbonate [ No CAS ]
[ 181633-42-1 ]
[ 374555-40-5 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane;	EXAMPLE 18 A mixture of <strong>[34551-41-2]1-chloro-5-bromoisoquinoline</strong> (68 mg) and [6-(2-methylpyridin-3-yloxy)pyridin-3-yl]amine (112 mg) was heated to 190 C. for 7minutes. After cooling to ambient temperature, the reaction mixture was taken up into a mixture of dichloromethane and an aqueous potassium carbonate solution (10%). The separated organic layer was washed with brine, dried over potassium carbonate and evaporated under reduced pressure. The residue was purified by a column chromatography on silica gel (60 ml) eluding with 0-5% methanol in dichloromethane to give (5-bromo-isoquinolin-1-yl)-[6-(2-methylpyridine-3-yloxy)pyridin-3-yl]amine (30 mg). APCI-mass; 407, 409 (m/z, [M+H]+) NMR (DMSO-d6, delta): 2.34 (3H, s), 7.14 (1H, d, J=8.9 Hz), 7.28-7.40 (2H, m), 7.45-7.65 (2H, m), 6.02-8.17 (2H, m), 8.25-8.37 (2H, m), 8.48 (1H, d, J=2.5 Hz), 8.54 (1H, d, J=8.3 Hz), 9.45 (1H, s).

Reference： [1]Patent: US2003/176454,2003,A1

11
[ 34551-41-2 ]
[ 215453-51-3 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 20 7-Bromo-1-chloroisoquinoline The title compound was prepared from a mixture of 5- and 7-bromoisoquinoline N-oxides and separated from 5-bromo-1-chloroisoquinoline by chromatography, to give a white solid. 1H (delta, CDCl3, 300 MHz) 7.5 (1H, d), 7.7 (1H, d), 7.8 (1H, d), 8.3 (1H, d), 8.5 (1H, s); LRMS 244, 246 (MH).

Reference： [1]Patent: US6248738,2001,B1

12
[ 34551-41-2 ]
hexanes-EtOAc [ No CAS ]
1-chloro-5-isoquinolinecarboxaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In THF-ether; N,N-dimethyl-formamide;	Preparation 44 1-chloro-5-isoquinolinecarboxaldehyde A solution of n-BuLi (1.76 mL, 2.5 M in hexanes, 4.4 mmol) was added to a stirred solution of <strong>[34551-41-2]5-bromo-1-chloroisoquinoline</strong> (Braye, E.; Eloy, F.; Hoogzand, C.; Lenaers, R. Eur. J. Med. Chem., Chim. Therap. 1974, 9, 197) (1.0 g, 4.12 mmol) in THF-ether (36 mL, 1:1) at -78 C. under N2. After 20 minutes, DMF (0.66 mL, 8.5 mmol) was added and after an additional 30 minutes at -78 C. the reaction was quenched with EtOH (3 mL) and warmed to room temperature. The mixture was diluted with ether (150 mL), washed with saturated NH4Cl (50 mL), brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using hexanes-EtOAc (95:5 to 50:50) as eluant to give 1-chloro-5-isoquinolinecarboxaldehyde (308 mg, 1.61 mmol) as a white solid. 1H (delta, CDCl3, 400 MHz) 7.9 (1H, dd), 8.25 (1H, d), 8.5 (1H, d), 8.7 (1H, d), 9.0 (1H, d), 10.4 (1H, s); LRMS 192, 194 (MH).

Reference： [1]Patent: US6248738,2001,B1

13
[ 34551-41-2 ]
[ 109-55-7 ]
[ 919363-10-3 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 100℃; for 0.133333h;Microwave irradiation;	To a microwave vial containing 5-bromo-l-chloroisoquinoline (Step 3, 0.300 g, 1.2 mmol), dissolved in pyridine (3 mL), was added Dimethylaminopropyl-amine (0.16 mL, 1.3 mmol). The mixture was placed into CEM Microwave for 8 minutes at 100 0C, while supplying 80 Watts of power via power-max. The mixture was diluted with DCM and water, and extracted with DCM (3 x 10 mL). Then dried organics (over sodium sulfate) was filtered, and concentrated in-vacuo. It was then purified by Amino-Propyl Silica-gel chromatography in MeOH/DCM. This gave tan colored oil, which was titled product (0.085 g, 0.3 mmol). MS (ESI pos. ion) m/z: 309; 310 (M+H). Calc'd Exact Mass for C14H18N3Br: 308

Reference： [1]Patent: WO2007/5668,2007,A2 .Location in patent: Page/Page column 33; 47

14
Br^(1-)*C₉H₅ClN₃⁽¹⁺⁾ [ No CAS ]
[ 34551-41-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen bromide; copper(I) bromide; In water; at 70 - 80℃; for 1.5h;	To a 500 mL round-bottomed flask containing l-chloroisoquinolin-5 -amine (Step 2, 5.8 g, 32.5 mmol) in H2O (33 mL) and 40% HBr (14 mL) chilled to -5 OC in an ice bath, was added a freshly prepared solution of (Sodium nitrate (2.47 g, 35.7 mmol) in 8mL OfH2O) drop-wise over 15 minutes. After the addition, the mixture was kept at 2 0C, while stirred an additional 20 minutes. Then urea (0.192 g, 3.2 mmol) was added in order to decompose excess nitrate in the reaction mixture. After an additional 5 minutes of stirring the diazonium salt mixture was transferred into a dropping funnel. The diazonium salt was added drop-wise into a heated (70 0C) solution of Copper (1) Bromide (4.66g, 32.5 mmol) in 40% HBr (30 mL)). After the addition, the mixture was heated to 80 0C for 1.5 hours. Then the mixture was allowed to cool to ambient temperature. The solid, which had formed in the reaction mixture, was collected by filtration. Then recrystallized from hot EtOAc and Hexanes, after drying, gave a brown crystalline solid, which was titled product (4.576 g, 18.9 mmol). MS (ESI pos. ion) m/z: 243 (M+H). Calc'd Exact Mass for C9H5NBrCl: 242.5

Reference： [1]Patent: WO2007/5668,2007,A2 .Location in patent: Page/Page column 33; 47

15
[ 34551-41-2 ]
2-(4-hydroxycyclohexylamino)-4-(5-(4-(1-isobutyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)isoquinolin-1-yl)benzamide [ No CAS ]

Reference： [1]Patent: US2013/296320,2013,A1

16
[ 34551-41-2 ]
1-chloro-5-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)isoquinoline [ No CAS ]

Reference： [1]Patent: US2013/296320,2013,A1

17
[ 34551-41-2 ]
4-(5-(5-aminopyridin-3-yl)isoquinolin-1-yl)-2-(4-hydroxycyclohexylamino)benzamide [ No CAS ]

Reference： [1]Patent: US2013/296320,2013,A1

18
[ 34551-41-2 ]
2-(4-hydroxycyclohexylamino)-4-(5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-yl)benzonitrile [ No CAS ]

Reference： [1]Patent: US2013/296320,2013,A1

19
[ 34551-41-2 ]
2-(ethylamino)-4-(5-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)isoquinolin-1-yl)benzamide [ No CAS ]

Reference： [1]Patent: US2013/296320,2013,A1

20
[ 34784-04-8 ]
[ 34551-41-2 ]

Yield	Reaction Conditions	Operation in experiment
33 g		To a solution of 2 (60 g, 288 mmoles) in methylene chloride (1.5 L) there are added (75 g, 436 mmoles) of 75% m-CPBA. The mixture is heated at 40 C. for 20 hours. After HPLC monitoring and return to ambient temperature, 75 g of sodium thiosulphate are added in the course of 10 minutes, followed by 300 mL of water. The whole is decanted, the organic phase is washed with a 1N sodium hydroxide solution, and the organic phase is dried by passage over MgSO4. Evaporation under reduced pressure yields a white solid (42 g), which is used without additional treatment in the following step. A solution of the intermediate that forms (37 g, 165 mmoles) in methylene chloride (900 mL) and POCl3 (37 mL) is stirred for 18 hours at 45 C. After HPLC and/or GC monitoring, the reaction mixture is concentrated in vacuo. The residue is treated carefully with water, and the aqueous phase is extracted with methylene chloride. The organic phase is washed carefully with a saturated NaHCO3 solution and then with a saturated aqueous NaCl solution. Evaporation under reduced pressure yields intermediate 123 (33 g) in the form of a beige solid, which can be used without additional treatment in the following step. 1H NMR (400 MHz-CDCl3): delta 8.35 (2d, 2H), 8.00 (2d, 2H), 7.55 (t, 1H) GC-EI (70 eV): M+.=241

Reference： [1]Patent: US2013/296320,2013,A1
[2]Patent: WO2016/201052,2016,A1
[3]Patent: US2017/137385,2017,A1 .Location in patent: Paragraph 0203; 0204; 0205; 0206
[4]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1074 - 1080

21
[ 34551-41-2 ]
[ 100-51-6 ]
1-(benzyloxy)-5-bromoisoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With Tris(3,6-dioxaheptyl)amine; potassium carbonate; potassium hydroxide; In toluene; at 120℃; for 1h;	A suspension of compound ( 1b) (0.242 g), benzyl alcohol (0.162 g), potassium hydroxide (0.224 g), potassium carbonate (0.138 g), and tris(2-(2-methoxyethoxy)ethyl)amine (0.032 ml) in toluene (6 ml) was stirred at 120 C. for 1 hour. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was then purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound ( 1c) (0.621 g, 99%) as a pale yellow solid.

Reference： [1]Patent: US2013/296320,2013,A1 .Location in patent: Paragraph 0181

22
[ 34551-41-2 ]
4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester [ No CAS ]
4-(5-bromoisoquinolin-1-yl)-2-(4-hydroxycyclohexylamino)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With sodium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 3h;Inert atmosphere;	Pd(PPh3)4 (1.39 g) was added to a solution of compound ( 1b) (5.83 g), 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester (7.80 g), and an aqueous sodium carbonate solution (2 M, 40 mL) in ethylene glycol dimethyl ether (80 mL) in a nitrogen atmosphere, and the mixture was stirred at 85 C. for 3 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound ( 2a) (14.8 g, yield: 62%) as a white solid

Reference： [1]Patent: US2013/296320,2013,A1 .Location in patent: Paragraph 0184

23
[ 34551-41-2 ]
1-benzyloxy-5-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)isoquinoline [ No CAS ]

Reference： [1]Patent: US2013/296320,2013,A1

24
[ 34551-41-2 ]
1-hydroxy-5-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)isoquinoline [ No CAS ]

Reference： [1]Patent: US2013/296320,2013,A1

25
[ 34551-41-2 ]
C₂₅H₂₁N₇ [ No CAS ]

Reference： [1]Patent: US2013/296320,2013,A1

26
[ 34551-41-2 ]
C₂₇H₂₅N₅O [ No CAS ]

Reference： [1]Patent: US2013/296320,2013,A1

27
[ 34551-41-2 ]
C₃₂H₃₃N₇O [ No CAS ]

Reference： [1]Patent: US2013/296320,2013,A1

28
[ 2081-44-9 ]
[ 34551-41-2 ]
C₁₄H₁₄BrNO₂ [ No CAS ]

Reference： [1]Patent: US2013/310391,2013,A1 .Location in patent: Paragraph 0328

29
[ 34551-41-2 ]
1-aminoisoquinoline-5-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2016/201052,2016,A1

30
[ 34551-41-2 ]
5-(aminomethyl)isoquinolin-1-amine [ No CAS ]

Reference： [1]Patent: WO2016/201052,2016,A1

31
[ 34551-41-2 ]
tert-butyl N-[(1-aminoisoquinolin-5-yl)methyl]carbamate [ No CAS ]

Reference： [1]Patent: WO2016/201052,2016,A1

32
[ 34551-41-2 ]
5-(aminomethyl)isoquinolin-1-amine hydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/201052,2016,A1

33
[ 34551-41-2 ]
(1R,8S)-N-[(1-aminoisoquinolin-5-yl)methyl]-12-(2-fluorophenyl)-15-oxatetra-cyclo[6.6.1.0^2,7. 0^9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2016/201052,2016,A1

34
[ 34551-41-2 ]
(1R,8S)-N-[(1-aminoisoquinolin-5-yl)methyl]-12-(2-cyano-4-methylphenyl)-15-oxatetracyclo[6.6.1.0^2,7.0^9,14] pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2016/201052,2016,A1

35
[ 34551-41-2 ]
C₁₂H₁₁NO₂ [ No CAS ]